Cardiovascular diseases are the first leading cause of mortality in human beings. Low-density lipoprotein cholesterol (LDL-C) has been shown as one of the major risk factors of cardiovascular diseases, while its effect is relatively independent and controllable. In the past twenty years, statin-based lipid-lowering drugs have been successfully used to reduce incidence of cardiovascular diseases.
Nevertheless, statins are not always effective, and there are different needs of hypolipidemic therapy. Some patients, especially those of familial hypercholesterolaemia (FH) do not respond to statins. In these patients, it's difficult to control LDL-C at a low level even with a high dosage of statins. Besides, statins are associated of side effects including myalgia and rhabdomyolysis, which makes them intolerable or only tolerable at a very low dosage for some of the patients in need of blood lipid control. Then, proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors were found as a novel class and a new option of medication for control of blood LDL-C concentration.
PCSK9 is a serine protease, which plays a role in modulation of low-density lipoprotein receptor (LDLR). It has been shown in vitro that the level of cell surface LDLR is decreased in HepG2 cells when treated with PCSK9 protein. In vivo experiments in mice suggested that an increased level of PCSK9 protein reduced LDLR expression in liver. At the same time, compared to normal mice, PCSK9-knock-out mice exhibited an increased level of LDLR. It has been shown that PCSK9 directly binds to LDLR to be internalized together via immunofluorescence in the process of endocytosis. Up till now, there is no direct evidence of extracellular LDLR degradation by PCSK9, and the mechanism for PSCK9 in lowering the LDLR protein level remains elusive.
Studies have shown that PCSK9 plays a role in modulation of LDL production. Expression or up-regulation of PCSK9 has been associated with increased plasma LDL cholesterol, while expression suppression or deficiency of PCSK9 with decreased plasma LDL cholesterol.
Therefore, it is of great significance to develop therapeutic PCSK9 antagonists that inhibit or antagonize PCSK9 activities and importantly, monoclonal antibodies that specifically bind to PCSK9. Largely, PCSK9 inhibitors currently under investigation include small interfering RNA (siRNA), antisense oligonucleotides (ASOs), monoclonal antibodies and fusion proteins with binding specificity generated from new platforms, such as fusion proteins generated by the Adnectin platform. Currently, the major PCSK9 inhibitors include siRNA drugs, such as RG7652 (Alnylam Pharmaceuticals/The Medicines Company); Adnectin fusion proteins, such as BMS-962476 (BMS); ASO drugs, such as ALN-PCS02 (Idera Pharmaceuticals); antibody drugs, such as Bococizumab (Pfizer/Rinat) and LGT-209(Novartis); etc.
However, as found in some animal experiments and clinical investigations, some monoclonal antibodies as PCSK9 inhibitors still have problems with specificity, affinity or side effects. Therefore, there is a need for improved novel anti-PCSK9 antibodies with better efficacy.